Antiemetic, 1-(benzimidazolyl-alkyl)-piperidine derivatives

ABSTRACT

Compounds of the class of 1-(benzazolylalkyl)piperidine derivatives useful as antiemetic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS:

This is a division of application Ser. No. 687,139, filed May 17, 1976now U.S. Pat. No. 4,066,772, filed Jan. 3, 1978; which in turn is acontinuation-in-part of Ser. No. 597,793, filed July 21, 1975, nowabandoned.

BACKGROUND OF THE INVENTION

In the prior art there may be found a number of benzazolylalkyl andindolylalkyl substituted piperidine derivatives and a number ofaminoalkyl substituted benzazoles some of them having pharmacological,e.g. antidepressant, anticonvulsant, antihistaminic or antispasmogenicactivities.

Among other points of difference, the subject compounds of thisinvention differ from such known compounds by the nature of respectivelythe benzazole and/or substituted piperidine moiety within theirstructure.

A number of the aforementioned prior art compounds may be found in thefollowing references:

Int. Pharmacopsychiat. 1968 (1), p. 214;

C.a., 64, 2093 b (1966);

C.a., 72, 111466 (1970);

C.a., 81, 120632 b (1974);

Fr. Pat. No. 2,042,321 (Derw. Fr. Week S16, Pharm. p. 12); and

Belg. Pat. No. 753,472.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel 1-(benzazolylalkyl)piperidine derivatives of this inventionmay structurally be represented by the following formula: ##STR1## andthe pharmaceutically acceptable acid addition salts thereof, wherein: R¹and R² are each independently selected from the group consisting ofhydrogen, halo, lower alkyl and trifluoromethyl;

B is a member selected from the group consisting of the bivalentradicals ##STR2## and said L being a member selected from the groupconsisting of hydrogen, lower alkyl, lower alkylcarbonyl and loweralkenyl, and said bivalent radicals being attached to the benzenenucleus with their heteroatom;

R³ is a member selected from the group consisting of hydrogen andmethyl;

m and n are each an integer of from 1 to 2 inclusive; and the radical##STR3## is a member selected from the group consisting of:

A. A RADICAL HAVING THE FORMULA ##STR4## wherein R⁴ is a member selectedfrom the group consisting of hydrogen and lower alkyl; and R⁵ and R⁶ areeach independently selected from the group consisting of hydrogen, halolower alkyl and trifluoromethyl;

b. a radical having the formula: ##STR5## wherein R⁷ and R⁸ are eachindependently selected from the group consisting of hydrogen, halo,lower alkyl and trifluoromethyl; Y is a member selected from the groupconsisting of O and S; M is a member selected from the group consistingof hydrogen, lower alkyl and lower alkylcarbonyl; and the dotted lineindicates that the double bond between the 3 and 4 carbon atoms of thepiperidine nucleus is optional, provided that when said Y is S thenthere is a single bond between said 3 and 4 carbon atoms of thepiperidine nucleus and then said M is hydrogen;

c. a radical having the formula: ##STR6## wherein R⁷ and R⁸ are eachindependently selected from the group consisting of hydrogen, halo,lower alkyl and trifluoromethyl; and

d. a radical having the formula: ##STR7## wherein R⁹ is selected fromthe group consisting of hydrogen, halo, lower alkyl and trifluoromethyl,and R¹⁰ is selected from the group consisting of hydrogen and halo.

As used herein "lower alkyl" may be straight or branch chained and havefrom 1 to 5 carbon atoms, such as, for example, methyl, ethyl, propyl,1-methylethyl, butyl, pentyl and the like; "lower alkenyl" may be astraight or branch chained alkenyl radical having from 2 to 5 carbonatoms, such as, for example, 1-methylethenyl, 2-propenyl, 2-butenyl,3-butenyl, 2-pentenyl and the like; and the term "halo" is generic tohalogens of atomic weight less than 127, i.e., fluoro, chloro, bromo andiodo.

Compounds of formula (I) which may be represented by the formula:##STR8## wherein R¹, R², R³, m, n and ##STR9## are as previously definedand B¹ is as defined for B, but other than --NH--C(S)--, areconveniently prepared by reacting an appropriate reactive ester offormula (II) wherein X is an appropriate reactive ester function derivedfrom the corresponding alcohol, such as, for example, halo,methanesulfonyl, 4-methylbenzenesulfonyl and the like, with anappropriate piperidine derivative of formula (III) wherein the ##STR10##group is as defined hereinabove. ##STR11##

The foregoing condensation reaction is preferably carried out in anappropriate organic solvent, such as, for example, a lower alkanol, e.g.methanol, ethanol, propanol, butanol and the like alcohols; an aromatichydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene, and the like;a ketone, e.g. 4-methyl-2-pentanone; an ether, e.g. 1,4-dioxane,1,1'-oxybisethane and the like; N,N-dimethylformamide; nitrobenzene; andthe like. The addition of an appropriate base, such as, for example, analkali metal or earth alkali metal carbonate or hydrogen carbonate, maybe utilized to pick up the acid that is liberated during the course ofthe reaction. A small amount of an appropriate metal iodide, e.g. sodiumor potassium iodide, may be added as a reaction promotor, especiallywhen the reactive ester of formula (II) is a chloride. Somewhat elevatedtemperatures are appropriate to enhance the rate of the reaction andpreferably the reaction is carried out at the reflux temperature of thereaction mixture. In this and following procedures, the reactionproducts are separated from the medium and, if necessary, furtherpurified by the application of methodologies known in the art.

Compounds within the scope of formula (I) which may be represented bythe formula: ##STR12## wherein R¹, R², m, n, R³ and ##STR13## are aspreviously defined may also be prepared starting from the correspondingcompounds of formula (IV) ##STR14## wherein P is an appropriateprotecting group, by the removal of said protecting group according toconventional procedures as known in the art. Examples of such protectinggroups are, among others, lower alkyloxycarbonyl,4-methylbenzenesulfonyl, methanesulfonyl and, preferably a substitutedethenyl group of the formula: ##STR15##

When the protecting group is lower alkyloxycarbonyl,4-methylbenzenesulfonyl or methanesulfonyl, it may easily be removed byalkaline hydrolysis, and when the protecting group is a substitutedethenyl group it is conveniently eliminated by subjecting theappropriate intermediate (IV) to acid hydrolysis. In carrying out saidacid hydrolysis to remove the substituted ethenyl group from (IV) a widevariety of protonic acids may be employed including mineral acids, suchas, for example, hydrochloric, hydrobromic, sulfuric, nitric andphosphoric acid, and organic acids such as, for example, acetic,propanoic and the like acids. Further the reaction may be carried out inreaction-inert organic solvents as commonly employed in such a type ofhydrolytic reactions, e.g., methanol, ethanol, 2-propanone and the like.

Compounds within the scope of formula (I) which may be represented bythe formula: ##STR16## wherein R¹, R², m, n, R³ and ##STR17## are aspreviously defined and B² is selected from the group consisting of--NH--C(O)--, --NH--C(S)-- and --N═CH--, may still be prepared bysubjecting an appropriate benzenediamine of formula (V) to ring closurewith an appropriate cyclizing agent, the nature of which depends on thenature of B² in the desired product. ##STR18##

The foregoing cyclization reaction may be performed following art-knownprocedures of preparing 1H-benzimidazoles,1,3-dihydro-2H-benzimidazol-2-ones, and1,3-dihydro-2H-benzimidazol-2-thiones starting from 1,2-benzenediamines.Suitable cyclizing agents which may advantageously be employed toprepare compounds (I-c) wherein B² stands for --NH--C(O)--, include, forexample, urea, carbonyl dichloride and alkali metal isocyanates, and thecyclisation reaction may be carried out following methodologiesgenerally known in the art. For example, when urea is used as thecyclizing agent the desired compounds are easily obtained by stirringand heating the reactants together in the absence of any solvent.

When B² in the desired compounds (I-c) stands for --NH--C(S)--, theremay be used cyclizing agents such as, for example, carbon disulfide,thiourea, carbonothioic dichloride, ammonium thiocyanate and the like,and when B² stands for --N═CH--, there may be used formic acid or anappropriate tri(alkyloxy)methane as a cyclizing agent.

In a manner similar to that described hereabove there may be preparedcompounds of the formula: ##STR19## wherein R¹, R², R³, R⁷, R⁸, m, n, B¹and Y are as previously defined, by cyclizing an appropriatebenzenediamine of formula (VI) with an appropriate cyclizing agent.##STR20##

In carrying out said cyclization reaction there may be used the samecyclizing agents as described herebefore for the preparation ofcompounds (I-c) starting from (V), more specifically for the preparationof compounds (I-c) wherein B² stands for respectively --NH--C(O)-- and--NH--C(S)--.

Still in a similar manner there may be prepared compounds of theformula: ##STR21## wherein R¹, R², R³, R⁷, R⁸, m and n are as previouslydefined and the two Y groups are both O or both S, starting from thecorresponding intermediates of formula (VII) by cyclizing bothbenzenediamine groups in said (VII) in one reaction step with anappropriate cyclizing agent as described hereinabove for the preparationof respectively 1,3-dihydro-1H-benzimidazol-2-ones and1,3-dihydro-1H-benzimidazol-2-thiones. ##STR22## Compounds having theformula: ##STR23## wherein R¹, R², R³, R⁷, R⁸, m, n and B¹ are aspreviously defined and M¹ is lower alkyl or lower alkylcarbonyl maystill be prepared by respectively N-alkylating or N-alcylating thecorresponding unsubstituted compound with an appropriate alkylating,respectively acylating agent following art-known methodologies. TheN-alkylation may e.g. be carried out by the reaction of theunsubstituted compound with an appropriate reactive ester derived froman appropriate lower alkanol, e.g., a halo-lower alkane, o a lower alkylmethanesulfonate or 4-methylbenzenesulfontate under similar conditionsas described hereinabove for the preparation of the compound (I-a)starting from (II) and (III). The acylation may be carried out byreacting the unsubstituted compound with an anhydride or acylhalidederived from the appropriate lower alkylcarboxylic acid followingstandard N-acylating procedures as known in the art.

When B¹ in the compounds (I-f) stands for --NH--C(O)--, it isappropriate to start from an appropriate compound of formula: ##STR24##which is then N-alkylated, respectively N-acylated as describedhereabove, whereafter the substituted ethenyl protecting group iseliminated by acid hydrolysis.

Those compounds of formula (I-f) wherein B¹ stands for --N(L)--C(O)--,said L being a lower alkyl or lower alkylcarbonyl radical identical withM¹, may still be prepared starting from an appropriate compound offormula (I-e) wherein Y stands for O, by alkylating, respectivelyacylating both 1H -benzimidazole groups thereof in one reaction step.

Compounds having the formula: ##STR25## may still be prepared startingfrom a corresponding compound of formula (I-d) wherein Y stands for S,(I-d-1), by S-alkylation of the latter according to standardS-alkylating procedures, e.g., by the reaction of (I-d-1) with anappropriate halo-lower alkane or with an appropriate di-(loweralkyl)sulfate.

The starting materials used in the foregoing preparations may beobtained following the procedures indicated hereafter.

Reactive esters of formula (II) which may be represented by the formula:##STR26## wherein R¹, R², R³, m, n, B² and X are as previously definedmay be prepared as follows:

An appropriately substituted 2-chloronitrobenzene of formula (VIII) isreacted with an appropriate aminoalkanol (IX) by refluxing the reactantstogether in an appropriate reaction-inert organic solvent such as, forexample, a lower alkanol, e.g., ethanol, 2-propanol, butanol and thelike, whereupon a [(2-nitrophenyl)amino]alkanol of formula (X) isobtained, which in turn is subjected to a nitro-to-amine reduction, e.g.by catalytic hydrogenation using Raney-nickel catalyst. The thusobtained [(2-aminophenyl)amino]alkanol of formula (XI) is then reactedwith an appropriate cyclizing agent as described hereinbefore for thepreparation of the compounds (I-c) starting from (V), and the thusobtained alcohol (XII) is subsequently converted into the desiredreactive ester (II-a) by the application of methodologies known in theart.

Halides are conveniently prepared by the reaction of (XII) with anappropriate halogenating agent such as, for example, sulfinyl chloride,sulfuryl chloride, phosphor pentachloride, phosphor pentabromide,phosphoryl chloride and the like. When the reactive ester is an iodide,it is preferably derived from the corresponding chloride or bromide bythe replacement of that halogen with iodine. Other reactive esters suchas methanesulfonates and 4-methylbenzenesulfonates are obtained by thereaction of the alcohol with an appropriate sulfonyl halide such as, forexample, methanesulfonyl chloride and 4-methylbenzenesulfonyl chloriderespectively.

The foregoing reactions are more clearly illustrated in the followingschematic representation. ##STR27##

Intermediates of formula (II) which may be represented by the formula##STR28## wherein R¹, R², R³, m, n and X are as previously defined andB³ is selected from the group consisting of --S--C(O)--, --O--C(O)--,--N═N--, --N═CH--, and --N(L¹)--C(O)-- wherein L¹ is lower alkyl, loweralkenyl, or lower alkylcarbonyl may also conveniently be prepared by theintroduction of the reactive ester side chain into a starting materialof the formula ##STR29## following procedures known in the art. Forexample, one may first introduce a hydroxyalkyl chain by N-alkylating(XIII) with an appropriate haloalkanol of formula (XIV) following commonN-alkylating procedures to obtain an alcohol of formula (XV), thehydroxyl group of which is subsequently converted into a reactive estergroup according to conventional procedures as previously described. Inplace of the haloalkanol (XIV) there may also be used atetrahydro-2H-pyran-2-yl ether derivative thereof, in which case thecorresponding ether derivative of (XV) is obtained, the ether functionof which is split open by acid hydrolysis, e.g., by stirring and heatingthe ether compound in diluted hydrochloric acid.

When the reactive ester (II-b) is a halide, (II-b-1), it mayalternatively be prepared by the reaction of (XIII) with an equivalentof an appropriate dihaloalkane (XVI), in the presence of an appropriatestrong base such as, for example, sodium methanolate, or following aMackosza procedure using aqueous alkali and a quaternary ammoniumcatalyst, e.g., N,N,N-triethylbenzenemethanaminium chloride, yieldingthe desired intermediate (II-b-1).

The foregoing procedure may be illustrated as follows. ##STR30##

Intermediates of the formula: ##STR31## wherein R¹, R², R³, m, n and Xare as previously defined may still be prepared by introducing thereactive ester side chain into a starting material of formula (XVII)##STR32## wherein P is an appropriate protecting group as previouslydefined, and thereafter eliminating the protecting group of the thusobtained (XIX) according to art-known procedures as describedhereinabove. The introduction of the reactive ester side chain may beperformed following similar procedures to those described hereabove forthe introduction of said chain into starting materials of formula(XIII). More particularly there may be first introduced a hydroxyalkylchain, whereafter the hydroxyl group of the thus obtained intermediate(XVIII) is converted into a reactive ester group to obtain (XIX), or,when the reactive ester is a halide, (XIX-a) said halide may be obtaineddirectly by the reaction of (XVII) with an appropriate dihaloalkane.When the protecting P is one subject to alkaline hydrolysis, e.g., alower alkyloxycarbonyl, methanesulfonyl or 4-methylbenzenesulfonylgroup, the N-alkylation reaction to introduce respectively thehydroxyalkyl or haloalkyl chain should be carried out undernon-hydrolytic conditions, using for example an appropriate metal basesuch as, for example, sodium hydride or sodium methanolate in anappropriate aprotic organic solvent such as, for example,N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphorictriamide.

The foregoing reactions are more clearly illustrated in the followingschematic representation. ##STR33##

Intermediates having the formula ##STR34## wherein R¹, R², R³ and X areas previously defined and L² is lower alkyl or lower alkenyl, said loweralkenyl having its unsaturation at the β, γ or Ε-position, may still beprepared as follows.

An appropriate intermediate of formula (II-c), wherein m and n are each1, (II-c-2), is treated with sodium metal in absolute ethanol whereby acyclic ether of formula (XX) is formed. The latter is subsequentlyreacted with an appropriate reactive ester L² X, (XXI), wherein L² and Xare as previously defined, e.g., by refluxing the reactants together inan appropriate organic solvent such as, for example, 2-propanone,whereby the desired intermediate (II-d) is obtained. ##STR35##

The compounds of formula (IV), used as intermediates in the preparationof the compounds (I-b), may generally be obtained by a condensationreaction of an intermediate of formula (XIX) with an appropriateintermediate of formula (III) under similar conditions to thosedescribed hereinabove for the preparation of the compounds (I-a)starting from (II) and (III).

    (xix) + (iii) → (iv)

those intermediates of formula (IV) wherein ##STR36## has the formula##STR37## and which are indicated as (IV-b) may still be prepared by thecondensation of an appropriate reactive ester of formula (XIX) with anappropriate N-(2-nitrophenyl)-4-piperidinamine of formula (XXII),followed by the reduction of the nitro group of the thus obtained(XXIII) according to standard nitro-to-amine reduction procedures, e.g.,by the reaction of the nitro compound with nascent hydrogen or bycatalytic hydrogenation in the presence of an appropriate catalyst suchas, for example, Raney-nickel, and cyclization of the resultingbenzenediamine (XXIV) with an appropriate cyclizing agent as describedhereinabove.

The foregoing reactions are illustrated in the following schematicrepresentation. ##STR38##

The starting materials of formula (XXII) herein may be preparedfollowing the procedures outlined in U.S. Pat. No. 3,910,930.

The intermediates of formula (V) are obtained by the condensation of anappropriate reactive ester of formula (XXV) with an appropriatepiperidine derivative of formula (II), followed by the reduction of thenitro group of the thus obtained intermediate (XXVI) to an amino groupaccording to standard nitro-to-amine reduction procedures. ##STR39## Thereactive esters of formula (XXV), used as starting materials herein areeasily prepared starting from an alcohol of formula (X) by theconversion of the hydroxyl function thereof into a reactive ester groupfollowing standard procedures as previously described herein.

The intermediates of formula (VI) may generally be prepared by thecondensation of an appropriate reactive ester of formula (II) with anappropriate N-(2-nitrophenyl)-4-piperidinamine of formula (XXII) andsubsequent reduction of the nitro group of the thus obtained (XXVII) toan amine group following standard nitro-to-amine reduction procedures aspreviously described.

It is to be noted that when the nitro-to-amine reduction is accomplishedby catalytic hydrogenation using palladium-on-charcoal catalyst theremay occur dehalogenation in compounds wherein aromatic halogensubstituents are present. ##STR40##

The intermediates of formula (VII) may similarly be prepared by thecondensation of a reactive ester of formula (XXV) with a piperidinederivative of formula (XXII) followed by the reduction of both nitrogroups in the thus obtained (XXVIII) according to standard procedures aspreviously indicated. ##STR41##

Starting materials of formula (III), represented by the formulas:##STR42## and methods of preparing the same may respectively be found inthe following references:

a. U.S. Pat. No. 3,238,216;

b. U.S. Pat. No. 3,161,645; Belg. Pat. No. 830,403;

c. U.S. Pat. No. 3,518,276; and U.S. Pat. No. 3,575,990.

Starting materials of formula (III) which are represented by theformulas: ##STR43## may generally be prepared starting from anappropriate N-(2-aminophenyl)-4-piperidinamine of formula:

The starting materials (III-d) are conveniently prepared by thecyclization of (XXIX) with an appropriate cyclizing agent e.g., carbondisulfide and subsequent removal of the lower alkyloxycarbonyl group ofthe thus obtained (XXX) by alkaline hydrolysis.

The starting materials (III-e) can be prepared by S-alkylating (XXX) asdescribed hereinabove followed by elimination of the loweralkyloxycarbonyl group of the resulting (XXXI).

The N-(2-aminophenyl)-4-piperidinamines of formula (XXIX), a number ofwhich are known compounds, may be prepared following the proceduresoutlined in U.S. Pat. No. 3,910,930 and Belg. Pat. No. 830,403.

The foregoing procedures are illustrated in the following schematicrepresentation. ##STR44##

The ultimate starting materials in all of the foregoing preparations aregenerally known or their preparation may be performed followingart-known procedures of preparing similar compounds.

For example, the preferred starting materials of formula (XVII) whereinP is an appropriately substituted ethenyl group, (XVII-a), an importantnumber of which are known compounds, may be prepared following theprocedures outlines in J. Chem. Soc., 1960, p. 308 and p. 314. Moreparticularly such compounds are conveniently prepared by the reaction ofan appropriate ester of the formula (XXXII) wherein R¹¹ and R¹² have thepreviously indicated meaning, with an appropriate benzenediamine offormula (XXXIII). Said reaction is preferably carried out by stirringand refluxing the reactants together in an appropriate reaction-inertorganic solvent with azeotropic water removal. Suitable reaction-inertorganic solvents for this purpose include, for example, aromatichydrocarbons such as benzene, methylbenzene, dimethylbenzene and thelike. ##STR45##

The intermediates of formulas (V), (VI) and (VII) are deemed to be noveland, as useful intermediates in the preparation of the desired compoundsof formula (I), they constitute an additional feature of this invention.

The compounds of this invention may be converted to theirtherapeutically useful acid addition salts by treatment with anappropriate acid, such as, for example, an inorganic acid, such ashydrohalic acid, e.g., hydrochloric, hydrobromic, and the like; andsulfuric acid, nitric acid, phosphoric acid and the like; or an organicacid, such as, for example, acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic,(Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, benzoic,3-phenyl-2-propenoic, α-hydroxybenzeneacetic, methanesulfonic,ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and thelike acids. Conversely the salt form can be converted by treatment withalkali into the free base form.

The compounds of formula (I) and the therapeutically active acidaddition salts thereof have been found to possess strong antiemeticactivity as is evidenced by their ability to block apomorphine-inducedvomiting in dogs. The method used is described previously by P. A. J.Janssen and C. J. E. Niemegeers in: Arzneim.-Forsch. (Drug Res.), 9,765-767 (1959).

The compounds listed below were administered subcutaneously to beagledogs at different doses and the animals were challenged 1 hourthereafter with a standard dose of 0.31 mg/kg (subcutaneous) ofapomorphine.

The tables below give the ED₅₀ values of a number of the compounds underconsideration. As used herein the ED₅₀ value represents the dose whichprotects 50% of the animals from emesis.

It is understood that the compounds shown in the tables are not listedfor the purpose of limiting the invention thereto, but only to exemplifythe outstanding antiemetic properties of all the compounds within thescope of formula (I).

                  TABLE I                                                         ______________________________________                                         ##STR46##                                                                                                        ED.sub.50                                 L           R.sup.1  R.sup.4 R.sup.5                                                                              mg/kg s.c.                                ______________________________________                                        H           H        H       H      0.03                                      H           5-Cl     H       H      0.05                                      H           5-CH.sub.3                                                                             H       H      0.06                                      CH.sub.3    H        H       H      0.08                                      CH.sub.2CHCH.sub.2                                                                        H        H       H      0.25                                      H           H        H       4-F    0.04                                      H           5-Cl     H       4-F     0.015                                    H           H        H       3-CF.sub.3                                                                            0.025                                    H           H        CH.sub.3                                                                              H       0.015                                    ______________________________________                                    

                                      table ii                                    __________________________________________________________________________     ##STR47##                                                                     l       r.sup.1                                                                           r.sup.2                                                                           r.sup.3                                                                          ##STR48##                                                                           r.sup.7                                                                          salt and Solvate form                                                                    ED.sub.50 mg/kg                       __________________________________________________________________________                                           s.c.                                   H       H   H   H                                                                                 ##STR49##                                                                          H  --         0.02                                   H       5-Cl                                                                              H   H  "     H  --         0.10                                   H       5-CH.sub.3                                                                        6-CH.sub.3                                                                        H  "     H  CH.sub.3CHOHCH.sub.3                                                                     0.45                                   H       H   H   CH.sub.3                                                                         "     5-Cl                                                                             --         0.06                                   H       H   H   H  "     5-Cl                                                                             --         0.01                                   H       5-Cl                                                                              H   H  "     5-Cl                                                                             --         0.12                                   CH.sub.3                                                                              H   H   H  "     5-Cl                                                                             --         0.16                                   CH.sub.2CHCH.sub.2                                                                    H   H   H  "     5-Cl                                                                             --         0.12                                   H       H   H   H                                                                                 ##STR50##                                                                          H  --         0.04                                   H       5-F H   H                                                                                 ##STR51##                                                                          5-Cl                                                                             HCl H.sub.2 O                                                                             0.004                                 H       5-CH.sub.3                                                                        H   H  "     5-Cl                                                                             HCl H.sub.2 O                                                                            0.12                                   C(CH.sub.3)CH.sub.2                                                                   H   H   H  "     5-Cl                                                                             --         0.20                                   H       5-CH.sub.3                                                                        H   H  "     H  HCl H.sub.2 O                                                                            0.20                                   __________________________________________________________________________

                  table iii                                                       ______________________________________                                         ##STR52##                                                                                                    ed.sub.50                                     l            r.sup.8  r.sup.9   mg/kg s.c.                                    ______________________________________                                        H            4-Cl     H         0.06                                          CH.sub.2CHCH.sub.2                                                                         4-Cl     H         0.50                                          H            4-Cl     3-CF.sub.3                                                                              0.015                                         ______________________________________                                    

                  table iv                                                        ______________________________________                                                                   ed.sub.50                                          compound                   mg/kg s.c.                                         ______________________________________                                         ##STR53##                 0.25                                                ##STR54##                 0.001                                               ##STR55##                 0.03                                                ##STR56##                 0.004                                               ##STR57##                 0.06                                                ##STR58##                 0.025                                               ##STR59##                 0.004                                              ______________________________________                                    

in view of their useful antiemetic activity, the subject compounds maybe formulated into various pharmaceutical forms for administrationpurposes. To prepare the pharmaceutical compositions of this invention,an effective antiemetic amount of the particular compound, in base oracid-addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable, preferably,for administration orally, rectally or by parenteral injection. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example,may be prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Acid additionsalts of (I), due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The amount of active ingredient per dosage unit will be from about 0.25mg to about 100 mg and, preferably from about 1 to about 50 mg.

The following formulations exemplify typical antiemetic pharmaceuticalcompositions in dosage unit form suitable for systemic administration toanimal and human subjects in accordance with the instant invention.

Oral drops: The following formulation provides 50 liters of an oral-dropsolution comprising 10 milligrams of5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-oneas the active ingredient (A.I.) per milliliter.

    ______________________________________                                        A.I.                 500      grams                                           2-hydroxypropanoic acid                                                                            0.5      liter                                           Sodium saccharin     1750     grams                                           Cocoa flavor         2.5      liters                                          Purified water       2.5      liters                                          Polyethylene glycol q.s. ad                                                                        50       liters.                                         ______________________________________                                    

The A.I. is dissolved in the 2-hydroxypropanoic acid and 1.5 liters ofthe polyethylene glycol at 60°-80° C. After cooling to 30°-40° C. thereare added 35 liters of polyethylene glycol and the mixture is stirredwell. Then there is added a solution of the sodium saccharin in 2.5liters of purified water and while stirring there are added the cocoaflavor and polyethylene glycol q.s. ad volume. The resulting solution isfilled into suitable containers.

Injectable solution: The following formulation provides 20 liters of aparenteral solution comprising 2 milligrams of5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-oneas the active ingredient per milliliter.

    ______________________________________                                        A.I.                      40 grams                                            2,3-dihydroxybutanedioic acid                                                                           20 grams                                            methyl 4-hydroxybenzoate  36 grams                                            propyl 4-hydroxybenzoate  4 grams                                             water for injection q.s. ad 20 liters                                         ______________________________________                                    

The methyl and propyl 4-hydroxybenzoates are dissolved in about 10liters of boiling water for injection. After cooling to about 50° C.there are added while stirring the 2,3-dihydroxybutanedioic acid andthereafter the A.I. The solution is cooled to room temperature andsupplemented with water for injection q.s. ad volume. The solution issterilized by filtration (U.S.P. XVII p. 811) and filled in sterilecontainers.

Oral solution: The following formulation provides 20 liters of an oralsolution comprising 5 milligrams of5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-oneas the active ingredient per teaspoonful (5 milliliters).

    ______________________________________                                        A.I.                  20     grams                                            2,3-dihydroxybutanedioic acid                                                                       10     grams                                            Sodium saccharin      40     grams                                            1,2,3-propanetriol    12     liters                                           Sorbitol 70% solution 3      liters                                           Methyl 4-hydroxybenzoate                                                                            9      grams                                            Propyl 4-hydroxybenzoate                                                                            1      gram                                             Raspberry essence     2      milliliters                                      Gooseberry essence    2      milliliters                                      Purified water q.s. ad 20 liers.                                              ______________________________________                                    

The methyl and propyl 4-hydroxybenzoates are dissolved in 4 liters ofboiling purified water. In 3 liters of this solution are dissolved firstthe 2,3-dihydroxybutanedioic acid and thereafter the A.I. The lattersolution is combined with the remaining part of the former solution andthe 1,2,3-propanetriol and the sorbitol solution are added thereto. Thesodium saccharin is dissolved in 0.5 liters of water and the raspberryand gooseberry essences are added. The latter solution is combined withthe former, water is added q.s. ad volume and the resulting solution isfilled in suitable containers.

Film-coated tablets: 10,000 Compressed tablets, each containing as theactive ingredient 10 milligrams of5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one,are prepared from the following formulation:

    ______________________________________                                        Tablet core:                                                                  A.I.                    100    grams                                          Lactose                 570    grams                                          Starch                  200    grams                                          Polyvinylpyrrolidone (Kollidon K 90)                                                                  10     grams                                          Microcrystalline cellulose (Avicel)                                                                   100    grams                                          Sodium dodecyl sulfate  5      grams                                          Hydrogenated vegetable oil (Sterotex)                                                                 15     grams                                          ______________________________________                                    

    ______________________________________                                        Coating:                                                                      Methyl cellulose (Methocel 60 HG)                                                                   10     grams                                            Ethyl cellulose (Ethocel 22 cps)                                                                    5      grams                                            1,2,3-Propanetriol    2.5    milliliters                                      Polyethylene glycol 6000                                                                            10     grams                                            Concentrated colour suspension                                                                      30     milliliters                                      (Opaspray K-1-2109)                                                           Polyvinylpyrrolidone (Povidone)                                                                     5      grams                                            Magnesium octadecanoate                                                                             2.5    grams                                            ______________________________________                                    

Preparation of tablet core: A mixture of the A.I., the lactose and thestarch is mixed well and thereafter humidified with a solution of thesodium dodecyl sulfate and the polyvinylpyrrolidone in about 200milliliters of water. The wet powder mixture is sieved, dried and sievedagain. Then there is added the microcrystalline cellulose and thehydrogenated vegetable oil. The whole is mixed well and compressed intotablets.

Coating: To a solution of the methyl cellulose in 75 milliliters ofdenaturated ethanol there is added a solution of the ethyl cellulose in150 milliliters of dichloromethane. Then there are added 75 millilitersof dichloromethane and the 1,2,3-propanetriol. The polyethylene glycolis molten and dissolved in 75 milliliters of dichloromethane. The lattersolution is added to the former and then there are added the magnesiumoctadecanoate, the polyvinylpyrrolidone and the concentrated coloursuspension and the whole is homogenised.

The tablet cores are coated with the thus obtained mixture in a coatingapparatus.

Suppositories: Hundred suppositories each containing 30 milligrams of5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-oneas the active ingredient are prepared from the following formulations:

    ______________________________________                                        A.I.                  3      grams                                            2,3-Dihydroxybutanedioic acid                                                                       3      grams                                            Polyethylene glycol 400                                                                             25     milliliters                                      Surfactant (Span)     12     grams                                            Triglycerides (Witepsol 555) q.s. ad                                                                300    grams                                            ______________________________________                                    

The A.I. is dissolved in a solution of the 2,3-dihydroxybutanedioic acidin the polyethylene glycol 400. The surfactant and the triglycerides aremolten together. The latter mixture is mixed well with the formersolution. The thus obtained mixture is poured into moulds at atemperature of 37°-38° C. to form the suppositories.

In view of the antiemetic activity of the subject compounds, it isevident that the present invention provides a method of inhibitingemesis in warm-blooded animals by the systemic administration of aneffective antiemetic amount of a compound of formula (I) and thepharmaceutically acceptable acid addition salts thereof in admixturewith a pharmaceutical carrier.

The following examples are intended to illustrate but not to limit thescope of the present invention. Unless otherwise stated all partstherein are by weight.

EXAMPLE I

A mixture of 100 parts of 1-chloro-2-nitro-4-(trifluoromethyl)benzene,90 parts of 3-amino-1-propanol and 200 parts of butanol is stirred andheated till reflux. Stirring at reflux is continued overnight. Thereaction mixture is cooled and evaporated. Water is added to the residueand the whole is acidified with a hydrochloric acid solution. Theproduct is extracted with methylbenzene. The extract is dried, filteredand evaporated. The solid residue is crystallized from petroleumether.The product is filtered off and dried, yielding 141 parts (100%) of3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol.

A mixture of 141 parts of3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol and 1200 partsof methanol is hydrogenated at normal pressure and at room temperaturewith 15 parts of Raney-nickel catalyst. After the calculated amount ofhydrogen is taken up, the catalyst is filtered off and the filtrate isevaporated. The residue is crystallized from 2,2'-oxybispropane,yielding 110 parts (100%) of3-{[2-amino-4-(trifluoromethyl)phenyl]amino}-1-propanol.

To a stirred mixture of 21 parts of3-{[2-amino-4-(trifluoromethyl)phenyl]amino}-1-propanol and 100 parts ofwater are added 14.4 parts of hydrochloric acid solution. The whole isstirred for 10 minutes at room temperature. After cooling to 0°-10° C.,there is added dropwise a solution of 18 parts of potassium cyanate in50 parts of water. Upon completion, stirring is continued for 2 hours.The precipitated product is filtered off and dried. Then it is meltedand the melt is stirred for 10 minutes. After cooling, it is dissolvedin trichloromethane while heating. The solution is filtered and theproduct is allowed to crystallize from the filtrate. It is filtered offand dried, yielding 8 parts (34%) of1,3-dihydro-1-(3-hydroxypropyl)-5-trifluoromethyl)-2H-benzimidazol-2-one.

To a stirred mixture of 23 parts of1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)-2H-benzimidazol-2-onein 150 parts of trichloromethane are added dropwise 32 parts of sulfinylchloride. Upon completion, the whole is heated to reflux and stirring iscontinued for 1 hour at reflux temperature. After cooling, the reactionmixture is evaporated and the residue is crystallized from2,2'-oxybispropane, yielding 14 parts (56%) of1-(3-chloropropyl)-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one.

EXAMPLE II

A mixture of 171 parts of 1-chloro-4-methyl-2-nitrobenzene, 150 parts of3-amino-1-propanol and 400 parts of butanol is stirred and refluxed for30 hours. The reaction mixture is evaporated and the residue is pouredonto water. The product is extracted with methylbenzene. The extract iswashed with water and with a hydrochloric acid solution 2N, dried,filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and 5% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated, yielding 70 parts (33%) of3-[(4-methyl-2-nitrophenyl)amino]-1-propanol as a residue.

A mixture of 70 parts of 3-[(4-methyl-2-nitrophenyl)amino]-1-propanoland 400 parts of methanol is hydrogenated at normal pressure and at roomtemperature with 10 parts of palladium-on-charcoal catalyst 10%. Afterthe calculated amount of hydrogen is taken up, the catalyst is filteredoff and the filtrate is evaporated, yielding 54 parts (91%) of3-[(2-amino-4-methylphenyl)amino]-1-propanol as a residue.

To a stirred and cooled solution of 54 parts of3-[(2-amino-4-methylphenyl)amino]-1-propanol in 30 parts of hydrochloricacid solution 10% and 200 parts of water is added dropwise a solution of28 parts of potassium cyanate in 50 parts of water at a temperaturebelow 10° C. Upon completion, stirring is continued first for 1 hour atroom temperature and further for 24 hours at reflux temperature. Aftercooling to room temperature, the product is extracted withtrichloromethane. The extract is washed with a hydrochloric acidsolution 5%, dried, filtered and evaporated. The residue is crystallizedfrom 4-methyl-2-pentanone, yielding 19.5 parts (31%) of1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one; mp.114.1° C.

To a stirred solution of 18.5 parts of1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325parts of dichloromethane are added 11.9 parts of N,N-diethylethanamine.Then there are added dropwise (slowly) 11.5 parts of methanesulfonylchloride. Upon completion, stirring is continued for 1 hour at refluxtemperature. After cooling, the reaction mixture is washed with water,dried, filtered and evaporated. The solid residue is crystallized from4-methyl-2-pentanone, yielding 15 parts (58%) of1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-onemethanesulfonate; mp. 125° C.

EXAMPLE III

A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of3-amino-1-propanol, 0.2 parts of potassium iodide and 200 parts ofbutanol is stirred and refluxed overnight. The butanol is removed byevaporation in vacuo and water is added to the residue. The product isextracted with 4-methyl-2-pentanone. The extract is washed a few timeswith water, dried, filtered and evaporated. The oily residue is purifiedby column-chromatography over silica gel using a mixture oftrichloromethane and 5% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated. The residue is triturated in2,2'-oxybispropane. The product is filtered off and crystallized from amixture of 2,2'-oxybispropane and 2-propanol, yielding 31.7 parts of3-[(4,5-dichloro-2-nitrophenyl)amino]-1-propanol; mp. 97° C.

A mixture of 39.7 parts of3-[(4,5-dichloro-2-nitrophenyl)amino]-1-propanol and 400 parts ofmethanol is hydrogenated at normal pressure and at room temperature with5 parts of Raney-nickel catalyst. After the calculated amount ofhydrogen is taken up, the catalyst is filtered off. The filtrate isacidified with 24 parts of a hydrochloric acid solution while stirring.The solvent is evaporated and the solid residue is stirred in2-propanol. The product is filtered off and dried in vacuo, yielding31.5 parts of 3-[(2-amino-4,5-dichlorophenyl)amino]-1-propanolhydrochloride; mp. 185° C.

To a stirred mixture of 31.2 parts of3-[(2-amino-4,5-dichlorophenyl)amino]-1-propanol hydrochloride in 200parts of water is added dropwise, during a 15 minutes-period, a solutionof 10.6 parts of potassium cyanate in 50 parts of water at a temperaturebetween 15° and 20° C. Upon completion, stirring is continued first for20 minutes at room temperature and further for 20 hours at reflux. Thereaction mixture is allowed to cool over week-end to room temperature.The precipitated product is filtered off and boiled in trichloromethane.The undissolved part is filtered off and boiled in 4-methyl-2-pentanone.After cooling, the product is filtered off and dried, yielding 14.5parts (48% ) of5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp.174.7° C. To a stirred mixture of 13.3 parts of5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 8parts of N,N-diethylethanamine and 260 parts of dichloromethane areadded dropwise 7.4 parts of methanesulfonyl chloride. Upon completion,stirring is continued for one hour at reflux temperature. The reactionmixture is washed with water, dried, filtered and evaporated. The solidresidue is shaken with acidified water and 4-methyl-2-pentanone. Thewhole is filtered (the filtrate is set aside) and the filter-cake isdried, yielding a first fraction of 6.2 parts of5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-onemethanesulfonate. The 4-methyl-2-pentanone-phase is separated from thefiltrate, dried, filtered and evaporated, yielding a second fraction of8 parts of5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-onemethanesulfonate as an oily residue.

EXAMPLE IV

A mixture of 100 parts of 1,2-dichloro-3-nitrobenzene, 95 parts of3-amino-1-propanol and 200 parts of butanol is stirred and refluxedovernight. The reaction mixture is cooled and evaporated. The residue istaken up in water and the product is extracted with methylbenzene. Theextract is washed with water, dried, filtered and evaporated, yielding115 parts of 3-[(2-chloro-6-nitrophenyl)amino]-1-propanol as a residue.

A mixture of 115 parts of 3-[(2-chloro-6-nitrophenyl)amino]-1-propanoland 400 parts of ethanol is hydrogenated at normal pressure and at roomtemperature with 12 parts of a Raney-nickel catalyst. After thecalculated amount of hydrogen is taken up, the catalyst is filtered offand the filtrate is evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and 5% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated, yielding 20 parts (20%) of3-[(2-amino-6-chlorophenyl)amino]-1-propanol as a residue.

To a stirred and cooled (10° C.) mixture of 20 parts of3-[(2-amino-6-chlorophenyl)amino]-1-propanol, 12 parts of a hydrochloricacid solution and 100 parts of water is added dropwise a solution of 9parts of potassium cyanate in 30 parts of water: Upon completion,stirring is continued first for 2 hours at room temperature and furtherovernight at reflux temperature. After cooling, the product is extractedwith trichloromethane. The extract is washed with a diluted hydrochloricacid solution, dried, filtered and evaporated. The residue iscrystallized from 4-methyl-2-pentanone, yielding 9 parts (41%) of4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one.

To a stirred mixture of 9 parts of4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one, 7 partsof N,N-diethylethanamine and 130 parts of dichloromethane are addeddropwise 12 parts of methanesulfonyl chloride (exothermic reaction:temperature rises to reflux). Upon completion, stirring is continued for1 hour at reflux temperature. The reaction mixture is cooled and pouredonto water. The organic phase is separated, washed with acidified water,dried, filtered and evaporated. The residue is crystallized from4-methyl-2-pentanone, yielding 9 parts (75%) of4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-onemethanesulfonate.

EXAMPLE V

A mixture of 34.6 parts of 3-[(4-chloro-2-nitrophenyl)amino]-1-propanoland 320 parts of ethanol is hydrogenated at normal pressure and at roomtemperature with 8 parts of Raney-nickel catalyst. After the calculatedamount of hydrogen is taken up, the catalyst is filtered off and thefiltrate is evaporated, yielding 30 parts of3-[(2-amino-4-chlorophenyl)amino]-1-propanol as an oily residue.

To a stirred solution of 40 parts of3-[(2-amino-4-chlorophenyl)amino]-1-propanol in 140 parts of water and24 parts of a hydrochloric acid solution 10N is added dropwise asolution of 18 parts of potassium isocyanate in 40 parts of water(exothermic reaction: temperature rises to 35° C.). Upon completion,stirring is continued first for 30 minutes at room temperature andfurther for 20 hours at reflux temperature. The reaction mixture isallowed to stirr over week-end without heating. The precipitated productis filtered off and treated with a diluted hydrochloric acid solution in4-methyl-2-pentanone. The whole is stirred and the layers are separated.The 4-methyl-2-pentanone-phase is washed with water, dried, filtered andevaporated, yielding 18 parts (32%) of5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp.148.8° C.

To a stirred and cooled (ice-water bath) mixture of 14.1 parts of5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 8 partsof N,N-diethylethanamine and 195 parts of dichloromethane are addeddropwise 7.8 parts of methanesulfonyl chloride. Upon completion,stirring is continued first for 15 minutes while still cooling anfurther for 1 hour at reflux temperature. The dichloromethane isevaporated and the residue is dissolved in 4-methyl-2-pentanone andwater while heating. The layers are separated and the organic phase isstirred with 100 parts of water, while cooling in an ice-bath. Theprecipitated product is filtered off and dried, yielding 10 parts (53%)of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-onemethanesulfonate; mp. 140° C.

EXAMPLE VI

A mixture of 20 parts of5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 34 partsof sulfinyl chloride and 300 parts of trichloromethane is stirred andrefluxed for 4 hours. The trichloromethane is evaporated and the residueis crystallized from 4-methyl-2-pentanone (activated charcoal). Theproduct is filtered off (the filtrate is set aside), yielding a firstfraction of 8.2 parts of5-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one. Thefiltrate, which was set aside, is concentrated and the concentrate isstirred with 2,2'-oxybispropane. The precipitated product is filteredoff and dried, yielding a second fraction of 8 parts of5-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one.

EXAMPLE VII

To a stirred mixture of 22.6 parts of6-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one and 300parts of trichloromethane are added dropwise 32 parts of sulfinylchloride. Upon completion, stirring is continued for 3 hours at reflux.After stirring with activated charcoal, the reaction mixture is filteredhot over hyflo. The filtrate is evaporated and the residue is dissolvedin methylbenzene. The solution is washed a few times with water, dried,filtered and evaporated. The oily residue is triturated in2,2'-oxybispropane. The solid product is filtered off and dried,yielding 19 parts (77.5%) of6-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one; mp. 122°C.

EXAMPLE VIII

To a stirred and heated mixture of 17.5 parts of1,3-dihydro-1-(2-propenyl)-2H-benzimidazol-2-one, 5 parts ofN,N,N-triethylbenzenemethanaminium chloride and 150 parts of a sodiumhydroxide solution 60% are added dropwise 20.5 parts of1-bromo-3-chloropropane at 60° C. Upon completion, stirring at 60° C. iscontinued for 5 hours. The reaction mixture is cooled, water is addedand the product is extracted with trichloromethane. The extract isdried, filtered and evaporated, yielding 21 parts (84%) of1-(3-chloropropyl)-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-2-one as aresidue.

EXAMPLE IX

To a stirred solution of 8.5 parts of1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one in 45 parts ofN,N-dimethylformamide are added portionwise 1.7 parts of a sodiumhydride dispersion of 78%. After stirring for 1 hour at roomtemperature, the whole is cooled to 0°-5° C. and 8.65 parts of1-bromo-3-chloropropane are added dropwise (slowly). Upon completion,stirring is continued for 3 hours at room temperature. The reactionmixture is poured onto crushed ice and the product is extracted withmethylbenzene. The extract is washed with water, dried, filtered andevaporated. The residue is crystallized from 2-propanol, yielding 5.5parts (44%) of1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one;mp. 115° C.

A solution of 13 parts of1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-onein 6 parts of a hydrochloric acid solution and 40 parts of ethanol isstirred for 2 hours at room temperature. The reaction mixture isevaporated and the solid residue is crystallized from 2-propanol,yielding 9.5 parts (90%) of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one; mp. 115° C.

EXAMPLE X

To a stirred and hot (55° C.) mixture of 22.2 parts of1,3-dihydro-5,6-dimethyl-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one,3 parts of N,N,N-triethylbenzenemethanaminium chloride and 112.5 partsof a sodium hydroxide solution 60% are added dropwise 15.8 parts of1-bromo-3-chloropropane (slightly exothermic reaction). Upon completion,stirring is continued for 5 hours at 55° C. After cooling, water isadded and the oily product is extracted with methylbenzene. The extractis dried, filtered and evaporated. The residue is crystallized from2,2'-oxybispropane, yielding, after drying, 25 parts (88.5%) of1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one;mp. 98° C.

A mixture of 25 parts of1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one,165 parts of a hydrochloric acid solution 6N and 160 parts of ethanol isstirred and refluxed for 6 hours. The reaction mixture is evaporated andthe residue is dissolved in trichloromethane. This solution is dried,filtered and evaporated. The residue is crystallized from a mixture of2,2'-oxybispropane and 2-propanol, yielding, after drying, 16 parts(94.7%) of1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one; mp.140° C.

EXAMPLE XI

A solution of 180 parts of 3-[(2-nitrophenyl)amino]-1-propanol in 200parts of methanol and 100 parts of a hydrochloric acid solution 10N ishydrogenated at normal pressure and at a temperature at 50° C. in thepresence of 5 parts of palladium-on-charcoal catalyst 10%. After thecalculated amount of hydrogen (3 moles) is taken up, hydrogenation isstopped. The catalyst is filtered off and the filtrate is evaporated.The residue (mainly 3-[(2-aminophenyl)amino]-1-propanol hydrochloride)is dissolved in 500 parts of water. To this solution is added a solutionof 88.8 parts of potassium isocyanate in 150 parts of water and thewhole is stirred and refluxed for 15 hours. The reaction mixture iscooled and the product is extracted with trichloromethane. The extractis dried and evaporated. The residue is dissolved in 250 parts ofboiling water, treated with activated charcoal and crystallized at roomtemperature. The precipitate is filtered off and recrystallized from 400parts of water, followed by recrystallization from ethyl acetate,yielding 58 parts of1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one hydrate; mp.48°-65° C.

To a solution of 52.5 parts of1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one hydrate in 200parts of pyridine is added dropwise 63 parts of methanesulfonylchloride. The mixture is stirred and cooled on the air for 2 hours. Thepyridine is evaporated. To the residue is added 500 parts of water andthe formed precipitate is filtered off. It is dissolved in 350 parts oftrichloromethane. This solution is dried over magnesium sulfate andevaporated. The residue is crystallized from 40 parts of methylbenzene,yielding 25.5 parts of1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate;mp. 118°-120° C.

To a solution of 0.5 parts of sodium in 40 parts of absolute ethanol areadded in the cold 5.4 parts of1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate.The whole is stirred until all solid enters solution. The solution isfurther stirred and refluxed for 2 hours. After cooling, the reactionmixture is filtered from some inorganic matter and the filtrate isevaporated. The residue is dissolved in 80 parts of methylbenzene,boiled with activated charcoal, filtered and the filtrate is evaporatedagain. The solid residue is washed with cold methylbenzene andcrystallized from 16 parts of methylbenzene, yielding 2.6 parts of3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazole; mp. 116.5°-118.5° C.

To a solution of 5.7 parts of3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazole in 80 parts of2-propanone is added 5.7 parts of iodomethane and the whole is stirredand refluxed for 2h. 50. Then there is added a second portion of 5.7parts of iodomethane and the whole is further stirred and refluxed for2h. 50. The solvent is evaporated, yielding1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one as an oilyresidue.

EXAMPLE XII

To a stirred mixture of 17.4 parts of1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, 5 parts ofN,N,N-triethylbenzenemethanaminium chloride and 180 parts of sodiumhydroxide solution 60% are added dropwise 21 parts of1-bromo-3-chloro-2-methylpropane while heating at 55° C. Uponcompletion, stirring at 55° C. is continued for 3 hours. The reactionmixture is cooled, poured onto water and the product is extracted withmethylbenzene. The extract is dried, filtered and evaporated, yielding24 parts (90.6%) of1-(3-chloro-2-methylpropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-oneas a residue.

A mixture of 12 parts of1-(3-chloro-2-methylpropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one,5 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 partsof 4-methyl-2-pentanone is stirred and refluxed for 20 hours withwater-separator. After cooling, water is added and the layers areseparated. The organic phase is dried, filtered and evaporated, yielding7 parts (72.9%) of5-chloro-1-[1-{3-[1,3-dihydro-3-(1-methylethenyl)-2-oxo-2H-benzimidazol-1-yl]-2-methylpropyl}-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-oneas an oily residue.

EXAMPLE XIII

A mixture of 4.6 parts of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of1-(p-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts of sodiumcarbonate, 0.2 parts of potassium iodide and 80 parts of4-methyl-2-pentanone is stirred and refluxed overnight. After cooling,the precipitated product is filtered off and triturated twice: first ina boiling mixture of 4-methyl-2-pentanone and 2-propanol and then inboiling methanol. It is filtered off again and crystallized from amixture of N,N-dimethylformamide and water, yielding 4.5 parts of8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one;mp. 215.4° C.

EXAMPLE XIV

Following the procedure of Example XIII and using therein equivalentamounts of the appropriate starting materials, the following compoundsare obtained:

8-[3-(6-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-onehemihydrate; mp. 233° C.;

1-(4-fluorophenyl)-8-[3-(1,3-dihydro-5,6-dimethyl-2-oxo-2H-benzimidazol-1-yl)propyl]-1,3,8-triazaspiro[4,5]decan-4-one;mp. 245.2° C.;

8-{3-[1,3-dihydro-2-oxo-3-(2-propenyl)-2H-benzimidazol-1-yl]-propyl}-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 114° C.; and

8-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-1-[3-(trifluoromethyl)phenyl]-1,3,8-triazaspiro[4,5]decan-4-one;mp. 198.2° C.

EXAMPLE XV

A mixture of 2.3 parts of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.31 parts of1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 3.2 parts of sodiumcarbonate, 0.1 parts of potassium iodide and 80 parts of4-methyl-2-pentanone is stirred and refluxed overnight. After cooling toroom temperature, water is added. The undissolved product is filteredoff and purified by column-chromatography over silica gel using amixture of trichloromethane and 10% of methanol as eluent. The purefractions are collected and the eluent is evaporated, yielding 0.9 parts(22%) of8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 228° C.

EXAMPLE XVI

Following the procedure of Example XV and using therein equivalentamounts of the appropriate starting materials, the following compoundsare obtained:

8-[3-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one;mp. 171.7° C.;

8-[3-(6-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 255°-256° C.; and

1-(4-fluorophenyl)-8-{3-[1,3-dihydro-2-oxo-5-(trifluoromethyl)-2H-benzimidazol-1-yl]-propyl}-1,3,8-triazaspiro[4,5]decan-4-one;mp. 259.7° C.

EXAMPLE XVII

A mixture of 4.8 parts of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5.6 parts of3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one hydrochloride, 7.4parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone isstirred and refluxed overnight with water-separator. The reactionmixture is cooled, water is added and the layers are separated. The4-methyl-2-pentanone-phase is dried, filtered and evaporated. Theresidue is purified by column-chromatography over silica gel using amixture of trichloromethane and 5% of methanol as eluent. The purefractions are collected and the eluent is evaporated. The residue istriturated in 4-methyl-2-pentanone. The solid product is filtered offand dried, yielding 4.1 parts (50%) of8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 186° C.

EXAMPLE XVIII

A mixture of 4.2 parts of4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-onemethanesulfonate, 2.5 parts of1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts of sodium carbonateand 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight.The reaction mixture is cooled and water is added. The precipitatedproduct is filtered off and crystallized twice from a mixture ofN,N-dimethylformamide and water, yielding 0.8 parts (17%) of8-[3-(7-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 258.4° C.

EXAMPLE XIX

A mixture of 4.9 parts of5-chloro-1,3-dihydro-2-oxo-2H-benzimidazole-1-propanol methanesulfonate,3.7 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 3.4 parts ofsodium carbonate and 90 parts of N,N-dimethylformamide is stirred andheated for 1 hour at 50°-60° C. The N,N-dimethylformamide is distilledoff and the residue is taken up in water. The product is extracted with4-methyl-2-pentanone. The extract is dried, filtered and evaporated. Theresidue is purified by column-chromatography over silica gel using amixture of trichloromethane and 10% of methanol as eluent. The purefractions are collected and the eluent is evaporated. The residuesolidifies on triturating in 4-methyl-2-pentanone. The product isfiltered off and crystallized twice: first from 2-propanol and then froma mixture of N,N-dimethylformamide and water, yielding 1.8 parts (25%)of8-[3-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 233.7° C.

EXAMPLE XX

A mixture of 5.68 parts of1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-onemethanesulfonate, 4.62 parts of1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 3.7 parts of sodiumcarbonate and 45 parts of N,N-dimethylformamide is stirred for 1 hour at60° C. The reaction mixture is cooled and poured onto water. Theprecipitated product is filtered off and purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and 10% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated. The residue is crystallized froma mixture of N,N-dimethylformamide and water, yielding 2 parts (24%) of8-[3-(1,3-dihydro-5-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 255.5° C.

EXAMPLE XXI

A mixture of 5 parts of1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.4 partsof 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 2.65 parts of sodiumcarbonate and 22.5 parts of N,N-dimethylformamide is stirred and heatedfor 2 hours at 70° C. The reaction mixture is cooled and poured ontowater, whereupon an oily precipitate is formed. The supernatant aqueousphase is decanted and the residual oil is dissoved in trichloromethane.The solution is dried, filtered and evaporated. The residue is purifiedby column-chromatography over silica gel using a mixture oftrichloromethane and 5% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated, yielding 1 part of8-[3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 164.4° C.

EXAMPLE XXII

A mixture of 8 parts of5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-onemethanesulfonate, 9.2 parts of1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one and 90 parts ofN,N-dimethylformamide is stirred and heated at 60° C. for one hour. Thereaction mixture is evaporated and water is added to the residue. Thewhole is alkalized with ammonium hydroxide and the product is extractedwith trichloromethane. The extract is dried, filtered and evaporated.The residue is purified by column-chromatography over silica gel using amixture of trichloromethane and 10% of methanol as eluent. The purefractions are collected and the eluent is evaporated. The solid residueis triturated in 4-methyl-2-pentanone. The product is filtered off anddried, yielding 2 parts of8-[3-(5,6-dichloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 275.2° C.

EXAMPLE XXIII

A mixture of 2.3 parts of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.5 parts of5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 3.2 partsof sodium carbonate, 0.1 parts of potassium iodide and 80 parts of4-methyl-2-pentanone is stirred and refluxed for 24 hours. The reactionmixture is cooled to room temperature and water is added. Theundissolved product is filtered off and purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and 10% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated. The residue is crystallized from4-methyl-2-pentanone. The product is filtered off and recrystallizedfrom a mixture of N,N-dimethylformamide and water, yielding 1.3 parts(30%) of5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 242.5° C.

EXAMPLE XXIV

A mixture of 5.4 parts of6-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 partsof 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4parts of sodium carbonate, 0.2 parts of potassium iodide and 200 partsof 4-methyl-2-pentanone is stirred and refluxed overnight withwater-separator. After cooling, water is added and the layers areseparated. The 4-methyl-2-pentanone-phase is dried, filtered andevaporated. The oily residue is purified by column-chromatography oversilica gel using a mixture of trichloromethane and 10% of methanol aseluent. The pure fractions are collected and the eluent is evaporated.The solid residue is crystallized from a mixture ofN,N-dimethylformamide and water, yielding 2 parts (22%) of6-chloro-1-{3-[4-5(chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-onehydrate; mp. 179.6° C.

EXAMPLE XXV

A mixture of 3.58 parts of1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one, 3.26parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5.3 partsof sodium carbonate, 0.2 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed for 24 hours withwater-separator. After cooling, water is added and the layers areseparated. The organic phase is dried, filtered and evaporated. Theresidue is crystallized from 2-propanol, yielding, after drying, 2.5parts of1-{3-[4-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one-2-propanolate;mp. 159° C.

EXAMPLE XXVI

A mixture of 5.6 parts of6-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 4.34parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 partsof sodium carbonate, 0.2 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed overnight withwater-separator. The reaction mixture is cooled and water is added. Theundissolved product is filtered off and crystallized from a mixture ofN,N-dimethylformamide and water. It is filtered off again, boiled inmethanol, filtered off while hot and dried, yielding 5.1 parts of6-chloro-1,3-dihydro-1-{3-[4-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-2H-benzimidazol-2-one;mp. 273° C.

EXAMPLE XXVII

Following the procedure of Example XXVI and using therein equivalentamounts of the appropriate starting materials, the following compoundsare obtained:

1-{3-[4-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 225° C.;

1,3-dihydro-1-{3-[4-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-5-(trifluoromethyl)-2H-benzimidazol-2-one;mp. 263.4° C.;

5-chloro-1-{3-[4-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 253°-255° C.; and

5-chloro-1-[1-{3-[1,3-dihydro-2-oxo-3-(2-propenyl)-2H-benzimidazol-1-yl]propyl}-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one;mp. 153.4° C.

EXAMPLE XXVIII

A mixture of 5 parts of1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.75 partsof 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 2.65parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide isstirred at 70°-80° C. for 2 hours. The reaction mixture is cooled,poured onto water and the precipitated product is filtered off. It isdissolved in trichloromethane. The solution is dried, filtered andevaporated. The residue is crystallized from 4-methyl-2-pentanone,yielding 3 parts (43%) of5-chloro-1-{1-[3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 166.5° C.

EXAMPLE XXIX

A mixture of 7.6 parts of5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-onemethanesulfonate, 5.5 parts of5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5 parts ofsodium carbonate and 63 parts of N,N-dimethylformamide is stirred andheated in an oil-bath at 50°-60° C. for 2 hours. The reaction mixture ispoured onto water. The precipitated product is filtered off, dried andpurified by column-chromatography over silica gel using a mixture oftrichloromethane and 10% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated. The solid residue iscrystallized from 4-methyl-2-pentanone. The product is filtered off andrecrystallized from a mixture of N,N-dimethylformamide and water. It isfiltered off again and dissolved in a mixture of 4-methyl-2-pentanoneand a small amount of N,N-dimethylformamide. The solution is filteredtill clear and the filtrate is concentrated to a volume of about 10parts. The concentrate is triturated in methanol. The precipitatedproduct is filtered off and dried, yielding 1.27 parts of5-chloro-1-{3-[4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 229°-236° C.

EXAMPLE XXX

To a stirred solution of 1 part of5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-onein 32 parts of ethanol is added a solution of 0.35 parts of(±)-2,3-dihydroxy-1,4-butanedioic acid in 8 parts of ethanol. Uponstirring, the product is allowed to crystallize. It is filtered off anddried, yielding 1 part of(±)-5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one2,3-dihydroxybutanedioate, ethanolate; mp. 153.5° C.

EXAMPLE XXXI

A solution of 7 parts of5-chloro-1-[1-{3-[1,3-dihydro-3-(1-methylethenyl)-2-oxo-2H-benzimidazol-1-yl]-2-methylpropyl}-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-onein 120 parts of ethanol is acidified with 2-propanol, previouslysaturated with gaseous hydrogen chloride. The whole is boiled for 5minutes. The reaction mixture is evaporated and the residue is taken upin water. The mixture is alkalized with a concentrated ammoniumhydroxide solution. The product is extracted with trichloromethane. Theextract is dried, filtered and evaporated. The residue is crystallizedfrom a mixture of 4-methyl-2-pentanone and ethanol. The product isfiltered off and dried, yielding 1.3 parts (19.7%) of5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-2-methylpropyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 244° C.

EXAMPLE XXXII

A mixture of 2.3 parts of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.15 parts of1,3-dihydro-1-(1,2,3,6-tetrahydro-4-pyridinyl)-2H-benzimidazol-2-one,3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 80parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours.After cooling to room temperature, water is added and the layers areseparated. The organic phase is dried, filtered and evaporated. Theresidue is purified by column-chromatography over silica gel using amixture of trichloromethane and 10% of methanol is eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from a mixture of N,N-dimethylformamide and water, yielding2.5 parts (64.5%) of1-{3-[3,6-dihydro-4-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-(2H)-pyridinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 206.6° C.

EXAMPLE XXXIII

A stirred solution of 1 part of5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-onein 20 parts of ethanol is saturated with gaseous hydrogen chloride. Theformed hydrochloride salt is allowed to crystallize while stirring. Itis filtered off and dried, yielding 0.6 parts (53%) of5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-onehydrochloride hydrate; mp. 195.7° C.

EXAMPLE XXXIV

A solution of 1 part of5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-onein 40 parts of ethanol is acidified with 2-propanol, previouslysaturated with gaseous hydrogen chloride. While cooling, the formedhydrochloride salt is allowed to crystallize, yielding 1 part (83%) of5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-onehydrochloride ethanolate; mp. 213.7° C.

EXAMPLE XXXV

A mixture of 6.7 parts of5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-onemethanesulfonate, 4.2 parts of 4-(4-chlorophenyl)-4-piperidinol, 3.2parts of sodium carbonate and 32 parts of 4-methyl-2-pentanone isstirred and heated at 50°-60° C. for 1.50 hours. The reaction mixture ispoured onto ice-water. The precipitated product is filtered off anddissolved in trichloromethane. The solution is washed with water, dried,filtered and evaporated. The solid residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and 10% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated. The solid residue is stirred ina small amount of trichloromethane. The product is filtered off andcrystallized from 4-methyl-2-pentanone, yielding 2 parts (24%) of5-chloro-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 190.8° C.

EXAMPLE XXXVI

A mixture of 3.58 parts of1-(3-chloropropyl)-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-one, 3.17parts of 4-(4-chlorophenyl)-4-piperidinol, 5.3 parts of sodiumcarbonate, 0.2 parts of potassium iodide and 160 parts of4-methyl-2-pentanone is stirred and refluxed for 24 hours withwater-separator. After cooling, water is added and the layers areseparated. The organic phase is dried, filtered and evaporated. Theresidue is converted into the hydrochloride salt in methanol and2-propanol. The salt is filtered off and dried, yielding 1.7 parts of1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-5,6-dimethyl-2H-benzimidazol-2-onehydrochloride; mp. 260.8° C.

EXAMPLE XXXVII

A mixture of 5.6 parts of6-chloro-1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 4.2 partsof 4-(4-chlorophenyl)-4-piperidinol, 6.4 parts of sodium carbonate, 0.2parts of potassium iodide and 200 parts of 4-methyl-2-pentanone isstirred and refluxed overnight with water-separator. After cooling,water is added and the layers are separated. The4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oilyresidue is purified by column-chromatography over silica gel using amixture of trichloromethane and 10% of methanol as eluent. The purefractions are collected and the eluent is evaporated. The solid residueis crystallized from 4-methyl-2-pentanone, yielding 3.5 parts of6-chloro-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 180.6° C.

EXAMPLE XXXVIII

A mixture of 2.3 parts of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.12 parts of4-(4-chlorophenyl)-4-piperidinol, 3.2 parts of sodium carbonate, 0.1parts of potassium iodide and 80 parts of 4-methyl-2-pentanone isstirred and refluxed for 36 hours. After cooling to room temperature,water is added and the layers are separated. The organic phase is dried,filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and 10% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated. The residue is crystallized frommethylbenzene, yielding 1 part (26%) of1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 134.2° C.

EXAMPLE XXXIX

A mixture of 5 parts of1-(3-chloropropyl)-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-2-one,3.17 parts of 4-(4-chlorophenyl)-4-piperidinol, 5.3 parts of sodiumcarbonate, 0.2 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed for 15 hours withwater-separator. After cooling, water is added and the layers areseparated. The organic phase is dried, filtered and evaporated. Theresidue is crystallized from 2-propanol, yielding, after drying, 3.5parts (54.8%) of 1-{3-[4-(4-chlorophenyl)4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-2-one;mp. 141.3° C.

EXAMPLE XL

A mixture of 5 parts of1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one,3.9 parts of 4-(4-fluorophenyl)-4-piperidinol, 5.3 parts of sodiumcarbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxedfor 48 hours with water-separator. The reaction mixture is cooled toroom temperature, water is added and the whole is alkalized with 15parts of a sodium hydroxide solution 60%. The layers are separated andthe organic phase is dried, filtered and evaporated. The residue ispurified by column-chromatography over silica gel using a mixture oftrichloromethane and 10% of methanol as eluent. The pure fractions arecollected and the eluent is evaporated. The oily residue is dissolved in2-propanone. The solution is acidified with 2-propanol, previouslysaturated with gaseous hydrogen chloride, and the whole is stirred andrefluxed for 15 minutes. The solvent is evaporated and the formedhydrochloride salt is dissolved in water. The free base is liberated inthe conventional manner with a diluted sodium hydroxide solution. Theproduct is extracted with 4-methyl-2-pentanone. The extract is dried,filtered and evaporated. The residue is crystallized from methylbenzene.The product is filtered off and dried, yielding 2.5 parts of1-{3-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 135.4° C.

EXAMPLE XLI

A mixture of 4.21 parts of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol, 5.3 parts ofsodium carbonate, 0.1 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed for 6 hours withwater-separator. The reaction mixture is cooled and water is added. Theorganic phase is separated, dried, filtered and evaporated. The residueis crystallized from 4-methyl-2-pentanone. The product is filtered offand dried, yielding 3.4 parts (41.6%) of1-[3-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one;mp. 189.2° C.

EXAMPLE XLII

Following the procedure of Example XIII and using equivalent amounts ofthe appropriate starting materials, the following compounds are stillobtained:

1-(4-chlorophenyl)-8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1,3,8-triazaspiro[4,5]decan-4-one;

1-(4-chlorophenyl)-8-[3-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1,3,8-triazaspiro[4,5]decan-4-one;

8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-2-methylpropyl]-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one;

8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-propyl]-1-(4-fluorophenyl)-3-methyl-1,3,8-triazaspiro[4,5]-decan-4-one;and

8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-3-ethyl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one.

EXAMPLE XLIII

Following the procedure of Example XXIII and using equivalent amounts ofthe appropriate starting materials, the following compounds are stillobtained:

5-chloro-1-{3-[4-(1,3-dihydro-5-methyl-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;

5-chloro-1-[3-{4-[1,3-dihydro-2-oxo-5(trifluoromethyl)-2H-benzimidazol-1-yl]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one;

1-{3-[4-(5,6-dichloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;

5-chloro-1-{3-[4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]-2-methylpropyl]-1,3-dihydro-2H-benzimidazol-2-one;

5-bromo-1-{3-[4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;and

1-{3-[4-(5-bromo-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one.

EXAMPLE XLIV

Following the procedure of Example XXXVIII and using equivalent amountsof the appropriate starting materials, the following compounds are stillobtained:

5-chloro-1-[3-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one;

5-chloro-1{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-2-methylpropyl}-1,3-dihydro-2H-benzimidazol-2-one;

5-bromo-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;

1-{3-[4-(4-bromophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;

1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)]propyl}-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidazol-2-one;

1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-5,6-dichloro-1,3-dihydro-2H-benzimidazol-2-one;and

5-chloro-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-2-one.

EXAMPLE XLV

To a stirred and refluxing mixture of 35 parts of4-fluoro-1,2-benzenediamine in 270 parts of dimethylbenzene is addeddropwise, during a 2 hours-period, a solution of 57 parts of ethylα-acetylbenzeneacetate in 90 parts of dimethylbenzene while meantime theformed water and the ethanol are distilled off (water-separator). Thereaction mixture is evaporated and the residue is crystallized from2-propanol. The product is filtered off and purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions are collected and the eluent is evaporated, yielding 11 partsof6-fluoro-1,3-dihydro-1-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one;mp. 190° C.

To a stirred and hot (50° C.) mixture of 15 parts of6-fluoro-1,3-dihydro-1-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one,3 parts of N,N,N-triethylbenzenemethanaminium chloride and 75 parts of asodium hydroxide solution 60% are added dropwise 11.1 parts of1-bromo-3-chloropropane (slightly exothermic reaction). Upon completion,stirring is continued for 4 hours at 60° C. The reaction mixture iscooled, water is added and the product is extracted with methylbenzene.The extract is dried, filtered and evaporated, yielding 20 parts (100%)of1-(3-chloropropyl)-5-fluoro-1,3-dihydro-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-oneas an oily residue.

EXAMPLE XLVI

A mixture of 30 parts of 1H-benzimidazol, 49 parts of2-(4-chlorobutoxy)tetrahydro-2H-pyran, 21 parts of potassium hydroxideand 200 parts of ethanol is stirred and refluxed overnight. The reactionmixture is cooled to room temperature, filtered and the filtrate isevaporated. The residue is stirred in water and acidified with a dilutedhydrochloric acid solution. The whole is stirred and heated for 30minutes in a water-bath. After cooling to room temperature, the productis extracted with methylbenzene. The aqueous phase is separated andalkalized with ammonium hydroxide. The product is extracted withdichloromethane. The extract is dried, filtered and evaporated, yielding50 parts of 1H-benzimidazole-1-butanol as an oily residue.

To a stirred mixture of 50 parts of 1H-benzimidazole-1-butanol and 375parts of trichloromethane are added dropwise 35.2 parts of sulfinylchloride. Upon completion, stirring is continued for 3 hours at refluxtemperature. The reaction mixture is evaporated. The residue is taken upin trichloromethane. The whole is washed with ammonium hydroxide and thesolvent is evaporated. The residue is purified by column-chromatographyover silica gel using trichloromethane as eluent. The pure fractions arecollected and the eluent is evaporated, yielding 22 parts (45%) of1-(4-chlorobutyl)-1H-benzimidazole as an oily residue.

EXAMPLE XLVII

A mixture of 84 parts of ethyl4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinecarboxylate and 750 partsof a hydrobromic acid solution 48% in water is stirred and refluxed for4 hours. The precipitated product is filtered off, washed with water andpetroleum-ether, and dried, yielding 71 parts (81%) ofN-(4-chloro-2-nitrophenyl)-4-piperidinamine hydrobromide; mp. 275° C.

A mixture of 105 parts of1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one,71 parts of N-(4-chloro-2-nitrophenyl)-4-piperidinamine hydrobromide, 53parts of sodium carbonate, 0.2 parts of potassium iodide and 320 partsof 4-methyl-2-pentanone is stirred and refluxed for 24 hours withwater-separator. The reaction mixture is cooled, water is added and thelayers are separated. The organic phase is dried, filtered andevaporated, yielding 98.5 parts (100%) of1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-oneas a residue.

A solution of 98.5 parts of1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-onein 360 parts of methylbenzene is acidified with 2-propanol, previouslysaturated with gaseous hydrogen chloride. After boiling for a while, anoil precipitates. The supernatant phase is decanted and the residual oilis suspended in water. The suspension is alkalized with a concentratedammonium hydroxide solution. The product is extracted withmethylbenzene. The extract is dried, filtered and evaporated. Theresidue is crystallized from 4-methyl-2-pentanone. The product isfiltered off and dried, yielding 68 parts (75.5%) of1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one.

A mixture of 21.5 parts of1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-oneand 240 parts of methanol is hydrogenated at normal pressure and at roomtemperature with 5 parts of Raney-nickel catalyst. After the calculatedamount of hydrogen is taken up, the catalyst is filtered off and thefiltrate is evaporated, yielding 20 parts (100%) of1-[3-{4-[(2-amino-4-chlorophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-oneas a residue.

EXAMPLE XLVIII

A mixture of 21.5 parts of1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-oneand 240 parts of methanol is hydrogenated at normal pressure and at roomtemperature with 10 parts of palladium-on-charcoal catalyst 10%. Afterthe calculated amount of hydrogen is taken up, the catalyst is filteredoff and the filtrate is evaporated, yielding 18.5 parts (100%) of1-[3-{4-[(2-aminophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-oneas a residue.

EXAMPLE IL

To a stirred mixture of 39.2 parts of 3-(2-nitrophenyl)amino-1-propanoland 225 parts of trichloromethane are added dropwise 35.7 parts ofsulfinyl chloride (exothermic reaction: the temperature rises to 45°C.). Upon completion, stirring is continued for 6 hours at refluxtemperature. The reaction mixture is evaporated, yielding 43 parts(100%) of N-(3-chloropropyl)-2-nitrobenzenamine as a residue.

A mixture of 43 parts of N-(3-chloropropyl)-2-nitrobenzenamine 47.8parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one,30.3 parts of N,N-diethylethanamine and 180 parts ofN,N-dimethylacetamide is stirred and heated for 6 hours at 100° C. Thereaction mixture is cooled and poured onto 1500 parts of water. Theprecipitated product is filtered off, washed with water and with2,2'-oxybispropane and dried, yielding 64 parts (78.3%) of5-chloro-1,3-dihydro-1-{1-[3-(2-nitrophenylamino)propyl]-4-piperidinyl}-2H-benzimidazol-2-one;mp. 220° C.

A mixture of 64 parts of5-chloro-1,3-dihydro-1-{1-[3-(2-nitrophenylamino)propyl]-4-piperidinyl}-2H-benzimidazol-2-onein 200 parts of methanol and 225 parts of tetrahydrofuran ishydrogenated at normal pressure and at room temperature with 10 parts ofRaney-nickel catalyst. After the calculated amount of hydrogen is takenup, the catalyst is filtered off over hyflo and the filtrate isevaporated. The residue is crystallized from a mixture of 2-propanol andethanol. The product is filtered off and dried, yielding 42 parts(70.5%) of1-[1-{3-[N-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-chloro-1,3-dihydro-2H-benzimidazol-2-one;mp. 196° C.

EXAMPLE L

A mixture of 4.21 parts of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of1-(4-chloro-3-methylphenyl)-1,3,8-triazaspiro[4,5]decan-4-one, 5.3 partsof sodium carbonate, 0.1 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed for 6 hours withwater-separator. After cooling, water is added and the layers areseparated. The organic phase is dried, filtered and evaporated. Theresidue is crystallized from a mixture of methanol andN,N-dimethylformamide. The product is filtered off and dried, yielding 3parts (36.7%) of1-(4-chloro-3-methylphenyl)-8-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-1,3,8-triazaspiro[4,5]decan-4-one;mp. 208.6° C.

EXAMPLE LI

A mixture of 6 parts of 1-(3-chloropropyl)-1H-benzimidazole, 4.6 partsof 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts of sodiumcarbonate, 0.1 parts of potassium iodide and 80 parts of4-methyl-2-pentanone is stirred and refluxed overnight. The reactionmixture is cooled, water is added and the layers are separated. Theorganic phase is dried, filtered and evaporated. The residue is purifiedby column-chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 4-methyl-2-pentanone, yielding 2 parts (25%) of8-[3-(1H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;mp. 191° C.

EXAMPLE LII

A mixture of 5.3 parts of1-(3-chloropropyl)-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one,4.3 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone isstirred and refluxed overnight with water-separator. After cooling,water is added and the layers are separated. The4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oilyresidue is purified by column-chromatography over silica gel using amixture of trichloromethane and methanol (90:10 by volume) as eluent.The pure fractions are collected and the eluent is evaporated, yielding6 parts (67%) of1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-oneas an oily residue.

EXAMPLE LIII

Following the procedure of Example LII and using equivalent amounts ofthe appropriate starting materials, the following compounds areprepared:

1-{3-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-oneas an oily residue; and

3-{3-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-oneas an oily residue.

EXAMPLE LIV

A mixture of 14 parts of1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one,12.58 parts of5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5.3 partsof sodium carbonate, 0.1 parts of sodium iodide and 80 parts of4-methyl-2-pentanone is stirred and refluxed for 24 hours. The reactionmixture is filtered and the filtrate is evaporated. The residue is takenup in 160 parts of 2-propanol and the whole is stirred and refluxedovernight with activated charcoal. The latter is filtered off over hyfloand the filtrate is allowed to cool. The precipitated product isfiltered off, yielding a first crude fraction of 12.5 parts. Thefiltrate is treated with 2,2'-oxybispropane. The mixture is filtered andthe filtrate is evaporated. The residue is triturated in 2-propanone.The product is filtered off, yielding a second crude fraction of 4.9parts. The combined crude crops (resp. 12.5 and 4.9 parts) arecrystallized from methylbenzene. The product is filtered off andrecrystallized from water, yielding 8.7 parts of5-chloro-1-[1-{3-[2,3-dihydro-3-(1-methylethenyl)-2-oxo-1H-benzimidazol-1-yl]propyl}-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one;mp. 165.2° C.

EXAMPLE LV

A mixture of 6 parts of1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one,12 parts of a hydrochloric acid solution, 30 parts of water and 40 partsof ethanol is stirred first for a while at 50° C. and further for 1 hourat room temperature. The reaction mixture is evaporated and the residueis crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol.The product is filtered off and dried, yielding 3.7 parts (40%) of1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-2H-benzimidazol-2-onehydrochloride hydrate; mp. 251.4° C.

EXAMPLE LVI

Following the procedure of Example LV there is prepared5-chloro-1-{1-[3-(2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-onehydrochloride hydrate; mp. 213.3° C., starting from1-{3-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one.

EXAMPLE LVII

A mixture of 6.4 parts of3-{3-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one,24 parts of a concentrated hydrochloric acid solution, 80 parts ofethanol and 50 parts of water is stirred for 1 hour at room temperature.The reaction mixture is evaporated and the residue is stirred inammonium hydroxide. The product is extracted with trichloromethane. Theextract is dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue istriturated in 4-methyl-2-pentanone. The product is filtered off andcrystallized from a mixture of N,N-dimethylformamide and water, yielding2.5 parts (40%) of5-chloro-1-{1-[3-(2,3-dihydro-6-methyl-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-onehemihydrate; mp. 195.4° C.

EXAMPLE LVIII

A mixture of 9 parts of 1-(3-chloropropyl)-1H-benzimidazole, 10 parts of5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 7.4 partsof sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred andrefluxed overnight. The reaction mixture is cooled, water is added andthe layers are separated. The organic phase is dried, filtered andevaporated. The residue is crystallized from 4-methyl-2-pentanone,yielding 2.9 parts (14%) of1-{1-[3-(1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one;mp. 224° C.

EXAMPLE LIX

A mixture of 6.7 parts of 1-(4-chlorobutyl)-1H-benzimidazole, 5.5 partsof 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5.3 parts ofsodium carbonate, 0.1 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed overnight. The reactionmixture is cooled, water is added and the layers are separated. Theorganic phase is dried, filtered and evaporated. The residue is purifiedtwice by column-chromatography over silica gel using first a mixture oftrichloromethane and methanol (95:5 by volume) and then a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 4-methyl-2-pentanone. The product is filtered off anddried, yielding 1.8 parts of1-{1-[4-(1H-benzimidazol-1-yl)butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 157.1° C.

EXAMPLE LX

A mixture of 4.7 parts of 3-(3-chloropropyl)-2(3H)-benzoxazolone, 5parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one,6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone isstirred and refluxed overnight with water-separator. After cooling,water is added and the layers are separated. The 4-methyl-2-pentanonephase is dried, filtered and evaporated. The residue is boiled in amixture of 4-methyl-2-pentanone, 2-propanol and methanol. The whole iscooled and the product is filtered off and dried, yielding 4 parts (47%)of5-chloro-1-{1-[3-(2-oxo-3(2H)-benzoxazolyl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 212.3° C.

EXAMPLE LXI

A mixture of 5.4 parts of 3-(3-bromopropyl)-2(3H)-benzothiazolone, 4.5parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one,5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200parts of 4-methyl-2-pentanone is stirred and refluxed for 3 hours withwater-separator. After cooling, water is added and the layers areseparated. The organic phase is dried, filtered and evaporated. Theresidue is crystallized from a mixture of 4-methyl-2-pentanone and2-propanone. The product is filtered off and dried, yielding 2.5 parts(31%) of5-chloro-1,3-dihydro-1-{1-[3-(2-oxo-3(2H)-benzothiazolyl)propyl]-4-piperidinyl}-2H-benzimidazol-2-one;mp. 184.1° C.

EXAMPLE LXII

A mixture of 5 parts of5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 3.7 partsof sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred andrefluxed with water-separator. Then there are added 4.8 parts of1-(3-bromopropyl)-1H-benzotriazole and stirring is continued overnightat reflux temperature. The reaction mixture is cooled, water is addedand the undissolved product is filtered off and set aside. The organicphase is separated from the filtrate, dried, filtered and evaporated.The residue is combined with the undissolved product (see above) andpurified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 4-methyl-2-pentanone, yielding 2 parts (25%) of1-{1-[3-(1H-benzotriazol-1-yl)propyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one;mp. 203.4° C.

EXAMPLE LXIII

A mixture of 38 parts of carbon disulfide, 6 parts of1-[1-{3-[N-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-chloro-1,3-dihydro-2H-benzimidazol-2-oneand 32 parts of ethanol is stirred and refluxed for 24 hours. Thereaction mixture is evaporated and the residue is crystallized fromethanol. The product is filtered off and recrystallized from a mixtureof N,N-dimethylformamide and water, yielding 3 parts (45.5%) of5-chloro-1-{1-[3-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 266.6° C.

EXAMPLE LXIV

A mixture of 4 parts of1-[1-{3-[N-(2-amino-5-chlorophenyl)amino]propyl}-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one,6 parts of a concentrated hydrochloric acid solution and 30 parts offormic acid is stirred and refluxed overnight. The reaction mixture isevaporated and water is added to the residue. The whole is alkalizedwith a diluted ammonium hydroxide solution and the product is extractedwith trichloromethane. The extract is dried, filtered and evaporated.The residue is crystallized from 4-methyl-2-pentanone. The product isfiltered off and recrystallized from 2-propanol, yielding 1.1 parts(27%) of1-{1-[3-(6-chloro-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 214.9° C.

EXAMPLE LXV

A mixture of 18.3 parts of1-[3-{4-[(2-aminophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one,65 parts of carbon disulfide and 60 parts of ethanol is stirred andrefluxed for 24 hours. The reaction mixture is evaporated. The residueis crystallized from ethanol. The product is filtered off and dried,yielding 4.5 parts (19.7%) of1-{3-[4-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 248.5° C.

EXAMPLE LXVI

A mixture of 20 parts of1-[3-{4-[(2-amino-4-chlorophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one,52 parts of carbon disulfide and 120 parts of ethanol is stirred andrefluxed for 24 hours. The reaction mixture is filtered after cooling,and the filtrate is evaporated. The residue is crystallized from2-propanol. The product is filtered off and recrystallized from ethanol,yielding, after drying, 7.5 parts (34%) of1-{3-[4-(5-chloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 254.3° C.

EXAMPLE LXVII

A mixture of 4.94 parts of1-(4-chlorobutyl)-1,3-dihydro-2H-benzimidazol-2-one, 4.23 parts of4-(4-chlorophenyl)-4-piperidinol, 5.3 parts of sodium carbonate, 0.1parts of potassium iodide and 200 parts of 4-methyl-2-pentanone isstirred and refluxed for 20 hours with water-separator. The reactionmixture is cooled, water is added and the layers are separated. Theorganic phase is dried, filtered and evaporated. The residue iscrystallized from 4-methyl-2-pentanone. The product is filtered off anddried, yielding 4 parts of1-{4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 160.6° C.

EXAMPLE LXVIII

A mixture of 4.86 parts of 1-(3-chloropropyl)-1H-benzimidazole, 4.24parts of 4-(4-chlorophenyl)-4-piperidinol, 5.3 parts of sodiumcarbonate, 0.1 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed for 20 hours withwater-separator. The reaction mixture is cooled, water is added and thelayers are separated. The organic phase is dried, filtered andevaporated. The residue is crystallized from 4-methyl-2-pentanone. Theproduct is filtered off and dried, yielding 5 parts (67.6%) of1-[3-(1H-benzimidazol-1-yl)propyl]-4-(4-chlorophenyl)-4-piperidinol; mp.160° C.

EXAMPLE LXIX

A mixture of 7 parts of1-(3-chloropropyl)-5-fluoro-1,3-dihydro-3-(1-methyl)-2-phenylethenyl)-2H-benzimidazol-2-one,5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one,4.25 parts of sodium carbonate, 0.1 parts of potassium iodide and 200parts of 4-methyl-2-pentanone is stirred and refluxed overnight. Themixture is cooled to room temperature, water is added and the layers areseparated. The organic phase is dried, filtered and evaporated. Theresidue is stirred and refluxed overnight with a solution of 55 parts ofa hydrochloric acid solution 6N in 40 parts of ethanol. The solvent isevaporated and the residue is taken up in water. The whole is alkalizedwith ammonium hydroxide and the product is extracted withtrichloromethane. The extract is dried, filtered and evaporated. Theresidue is purified by column-chromatography over silica gel using amixture of trichloromethane and methanol (95:5 by volume) as eluent. Thepure fractions are collected and the eluent is evaporated. The residueis converted into the hydrochloride salt in 2-propanol. The salt isfiltered off and dried, yielding 1.2 parts of1-{3-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-5-fluoro-1,3-dihydro-2H-benzimidazol-2-onehydrochloride hydrate; mp. 250° C.

EXAMPLE LXX

10.2 Parts of5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-oneare converted into the (+)-2,3-dihydroxybutanedioate salt in 100 partsof water at reflux temperature. The solution is treated for 10 minuteswith a mixture of 0.5 parts of activated charcoal and 0.2 parts ofhyflo. The latter is filtered off over hyflo and the filtrate is cooledtill an oily precipitate is formed. The oily product solidifies uponheating for a while. The whole is allowed to cool to room temperatureand stirred for 3 hours at this temperature. The product is filteredoff, washed with water and dried in vacuo for 18 hours at 60° C.,yielding 10.24 parts (85.3%) of5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-onehemi-[R-(R',R')](+)-2,3-dihydroxybutanedioate hydrate; mp. 184.1° C.;[α] = + 5.13° (c = 1% CH₃ OH).

EXAMPLE LXXI

A mixture of 9.25 parts of1-(4-chlorobutyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one,7.55 parts of5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 10.6 partsof sodium carbonate, 0.1 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed for 18 hours. Aftercooling, water is added and the layers are separated. The organic phaseis dried, filtered and evaporated. The residue is dissolved in 40 partsof ethanol and the solution is acidified with 30 parts of a concentratedhydrochloric acid solution. The whole is stirred for 30 minutes and thesolvent is evaporated. The residue is suspended in water and thesuspension is alkalized with ammonium hydroxide. The product isextracted with trichloromethane. The extract is dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (90:10 by volume)as eluent. The pure fractions are collected and the eluent isevaporated. The residue is crystallized from a mixture ofN,N-dimethylformamide and water. The product is filtered off and dried,yielding 6.5 parts (46%) of5-chloro-1-{1-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)butyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-onehemihydrate; mp. 258° C.

EXAMPLE LXXII

A mixture of 4.15 parts of1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one,3.9 parts of 1-(1-methylethyl)-3-(4-piperidinyl)-2H-benzimidazol-2-one,3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 120parts of 4-methyl-2-pentanone is stirred and refluxed overnight. Thereaction mixture is cooled to room temperature, water is added and thelayers are separated. The organic phase is dried, filtered andevaporated. The residue is stirred for 30 minutes with a solution of 12parts of a concentrated hydrochloric acid solution in 40 parts ofethanol. The solvent is evaporated and the residue is suspended inwater. The suspension is alkalized with a diluted ammonium hydroxidesolution and the product is extracted with trichloromethane. The extractis dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 4-methyl-2-pentanone. The product is filtered off anddried, yielding 4.2 parts (64%) of1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-3-(1-methylethyl)-2H-benzimidazol-2-one;mp. 174.3° C.

EXAMPLE LXXIII

A mixture of 2.21 parts of1-{3-[4-(5-chloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one,0.71 parts of iodomethane, 0.28 parts of sodium methanolate and 40 partsof methanol is stirred overnight at room temperature. The reactionmixture is evaporated. The residue is stirred with water and the productis extracted with trichloromethane. The extract is dried, filtered andevaporated. The residue is crystallized from 4-methyl-2-pentanone. Theproduct is filtered off and dried, yielding 1.1 parts of1-[3-{4-[5-chloro-2-(methylthio)-1H-benzimidazol-1-yl]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one;mp. 196.1° C.

EXAMPLE LXXIV

A mixture of 5 parts of5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one,10 parts of acetic acid anhydride and 90 parts of methylbenzene isstirred and refluxed overnight. The reaction mixture is cooled, water isadded and the whole is alkalized with a diluted sodium carbonatesolution. The layers are separated and the organic phase is dried,filtered and evaporated. The residue is crystallized from methylbenzene.The product is filtered off and recrystallized from methylbenzene,yielding 4.5 parts of3-acetyl-5-chloro-1-{1-[3-(3-acetyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one;mp. 185.3° C.

We claim:
 1. A chemical compound selected from the group consisting of a1-(benzimidazolylalkyl)piperidine derivative having the formula:##STR60## and the pharmaceutically acceptable acid addition saltsthereof, wherein: R¹ and R² are each independently selected from thegroup consisting of hydrogen, halo, lower alkyl and trifluoromethyl;R³is a member selected from the group consisting of hydrogen and methyl; mand n are each an integer of from 1 to 2 inclusive; and the radical##STR61## is a member selected from the group consisting of: a. aradical having the formula: ##STR62## wherein R⁴ is a member selectedfrom the group consisting of hydrogen and lower alkyl; and R⁵ and R⁶ areeach independently selected from the group consisting of hydrogen, halo,lower alkyl and trifluoromethyl;b. a radical having the formula:##STR63## wherein R⁷ and R⁸ are each independently selected from thegroup consisting of hydrogen, halo, lower alkyl and trifluoromethyl; Yis a member selected from the group consisting of O and S; M is a memberselected from the group consisting of hydrogen, lower alkyl and loweralkylcarbonyl; and the dotted line indicates that the double bondbetween the 3 and 4 carbon atoms of the piperidine nucleus is optional,provided that when said Y is S, then there is a single bond between said3 and 4 carbon atoms of the piperidine nucleus, and then said M ishydrogen; and c. a radical having the formula: ##STR64## wherein R⁷ andR⁸ are each independently selected from the group consisting ofhydrogen, halo, lower alkyl, and trifluoromethyl.
 2. A chemical compoundselected from the group consisting of8-[3-(1H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-oneand the pharmaceutically acceptable acid addition salts thereof.
 3. Apharmaceutical composition comprising a pharmaceutically acceptableinert carrier material and as an active ingredient an effectiveantiemetic amount of a chemical compound selected from the groupconsisting of a 1-(benzimidazolylalkyl)piperidine derivative having theformula: ##STR65## and the pharmaceutically acceptable acid additionsalts thereof, wherein: R¹ and R² are each independently selected fromthe group consisting of hydrogen, halo, lower alkyl andtrifluoromethyl;R³ is a member selected from the group consisting ofhydrogen and methyl; m and n are each an integer of from 1 to 2inclusive; and the radical ##STR66## is a member selected from the groupconsisting of: a. a radical having the formula: ##STR67## wherein R⁴ isa member selected from the group consisting of hydrogen and lower alkyl;and R⁵ and R⁶ are each independently selected from the group consistingof hydrogen, halo, lower alkyl and trifluoromethyl;b. a radical havingthe formula: ##STR68## wherein R⁷ and R⁸ are each independently selectedfrom the group consisting of hydrogen, halo, lower alkyl andtrifluoromethyl; Y is a member selected from the group consisting of Oand S; M is a member selected from the group consisting of hydrogenlower alkyl and lower alkylcarbonyl; and the dotted line indicates thatthe double bond between the 3 and 4 carbon atoms of the piperidinenucleus is optional, provided that when said Y is S, then there is asingle bond between said 3 and 4 carbon atoms of the piperidine nucleus,and the said M is hydrogen; and c. a radical having the formula:##STR69## wherein R⁷ and R⁸ are each independently selected from thegroup consisting of hydrogen, halo, lower alkyl, and trifluoromethyl. 4.A pharmaceutical composition in dosage unit form comprising per dosageunit an effective antiemetic amount of a compound selected from thegroup consisting of a 1-(benzimidazolylalkyl)piperidine derivativehaving the formula: ##STR70## and the pharmaceutically acceptable acidaddition salts thereof, wherein: R¹ and R² are each independentlyselected from the group consisting of hydrogen, halo, lower alkyl andtrifluoromethyl;R³ is a member selected from the group consisting ofhydrogen and methyl; m and n are each an integer of from 1 to 2inclusive; and the radical ##STR71## is a member selected from the groupconsisting of: a. a radical having the formula: ##STR72## wherein R⁴ isa member selected from the group consisting of hydrogen and lower alkyl;and R⁵ and R⁶ are each independently selected from the group consistingof hydrogen, halo, lower alkyl and trifluoromethyl;b. a radical havingthe formula: ##STR73## wherein R⁷ and R⁸ are each independently selectedfrom the group consisting of hydrogen, halo, lower alkyl andtrifluoromethyl; Y is a member selected from the group consisting of Oand S; M is a member selected from the group consisting of hydrogen,lower alkyl and lower alkylcarbonyl; and the dotted line indicates thatthe double bond between the 3 and 4 carbon atoms of the piperidinenucleus is optional, provided that when said Y is S, then there is asingle bond between said 3 and 4 carbon atoms of the piperidine nucleus,and then said M is hydrogen; and c. a radical having the formula:##STR74## wherein R⁷ and R⁸ are each independently selected from thegroup consisting of hydrogen, halo, lower alkyl, and trifluoromethyl. 5.The pharmaceutical composition of claim 4 wherein said pharmaceuticalcarrier is a solid, ingestible carrier.
 6. The pharmaceuticalcomposition of claim 4 wherein said pharmaceutical carrier is a liquid,ingestible carrier.
 7. The pharmaceutical composition of claim 4 whereinsaid pharmaceutical carrier is a sterile liquid suitable for parenteraluse.
 8. A pharmaceutical composition in dosage unit form comprising perdosage unit an effective antiemetic amount of a compound selected fromthe group consisting of8-[3-(1H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-oneand the pharmaceutically acceptable acid addition salts thereof inadmixture with a pharmaceutically acceptable carrier.
 9. A method ofinhibiting emesis which comprises the systemic administration inwarm-blooded animals in need of such treatment of an effectiveantiemetic amount of a compound selected from the group consisting of a1-(benzimidazolylalkyl)piperidine derivative having the formula:##STR75## and the pharmaceutically acceptable acid addition saltsthereof, wherein: R¹ and R² are each independently selected from thegroup consisting of hydrogen, halo, lower alkyl and trifluoromethyl;R³is a member selected from the group consisting of hydrogen and methyl; mand n are each an integer of from 1 to 2 inclusive; and the radical##STR76## is a member selected from the group consisting of: a. aradical having the formula: ##STR77## wherein R⁴ is a member selectedfrom the group consisting of hydrogen and lower alkyl; and R⁵ and R⁶ areeach independently selected from the group consisting of hydrogen, halo,lower alkyl and trifluoromethyl;b. a radical having the formula:##STR78## wherein R⁷ and R⁸ are each independently selected from thegroup consisting of hydrogen, halo, lower alkyl and trifluoromethyl; Yis a member selected from the group consisting of O and S; M is a memberselected from the group consisting of hydrogen, lower alkyl and loweralkylcarbonyl; and the dotted line indicates that the double bondbetween the 3 and 4 carbon atoms of the piperidine nucleus is optional,provided that when said Y is S, then there is a single bond between said3 and 4 carbon atoms of the piperidine nucleus, and then said M ishydrogen; and c. a radical having the formula: ##STR79## wherein R⁷ andR⁸ are each independently selected from the group consisting ofhydrogen, halo, lower alkyl, and trifluoromethyl.
 10. A method ofinhibiting emesis which comprises the systemic administration inwarm-blooded animals in need of such treatment of an effectiveantiemetic amount of a compound selected from the group consisting of8-[3-(1H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-oneand the pharmaceutically acceptable acid addition salts thereof inadmixture with a pharmaceutical carrier.